The long-term objectives of our research program are to model the pathophysiology of mental stress ischemia (MSI), and to use this model to test treatments that improve prognosis for the approximately 50% of CAD patients who are at risk for poor outcomes because of this ischemic syndrome. During the current funding period we have identified a network of brain regions, including prefrontal, sub-cortical and limbic areas, that serve executive, affective, attentional, and memory functions, and that is uniquely activated during mental vs. exercise related ischemia, and during laboratory stress in patients who are dispositionally prone toward hostility and anger. We have also found that perturbations in myocardial blood flow appear necessary for the provocation of MSI. Pilot data regarding, a) laboratory stress-induced changes in autonomic balance and associated increases in levels of the inflammatory cytokine TNF-a, and, b) the potentiating effect that threshold levels of ET-1 have on sympathetic activity in the provocation of MSI, provide a direction for the articulation of a complete "neurocardiac model" of this ischemic syndrome. The aims of this proposal are to tie our observations regarding CMS activity to our observations regarding myocardial blood flow during mental stress by, 1) assessing key intermediary autonomic pathways during mental stress in patients with CAD, and 2) determining the contributions of dispositional (hostility) and reactive factors (state anger) to the provocation of ischemia during mental stress. Hypotheses relate to, a) MS induced alterations in autonomic tone, accompanying increases in levels of circulating vasoactive peptides (e.g., TNF-a, ET-1) and patterns of CMS activity during MSI;and, b) the relationship of dispositional factors to reactive factors in the prediction of MSI and the prediction of accompanying increases in levels of circulating vasoactive peptides during mental stress. Public Health Relevance: Mental stress ischemia is associated with increased risk of cardiac events and decreased survival. The complete modeling of this ischemia will help efforts to define and test treatments to reduce the risk of MSI and improve medical outcomes for patients with coronary disease.